The application claims the benefit of U.K. patent application No. 9922963.5, filed Sep. 28, 1999.
The present invention relates to the hemisulphate salt of the anti-migraine drug 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole having formula (I): 
Specifically, the invention relates to a particular polymorphic form of said hemisulphate salt, to processes for the preparation of said form, to pharmaceutical compositions containing same and to its use in medicine, particularly the treatment of conditions for which an agonist of 5-HT1 receptors is indicated, for example, migraine.
International Patent Application PCT/US91/07194 describes a series of 3,5-disubstituted indoles and pharmaceutically acceptable salts thereof. The hemisuccinate salt of 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole is specifically described therein as a non-crystalline foam unsuitable for the preparation of pharmaceutical compositions, but subsequent studies indicated that the hemisulphate, hydrochloride and hydrobromide salts were all sufficiently crystalline and high-melting to be considered for this purpose.
Thus European Patent 0776323 is concerned with specific polymorphic forms of the corresponding hydrobromide salt and describes for the purposes of comparison two polymorphs of the hemisulphate salt which are referred to therein as the xcex1- and xcex2-forms. In contrast to the polymorphs of the hydrobromide salt, the xcex1- and xcex2-polymorphs of the hemisulphate salt are variously described as hygroscopic, polymorphically unstable and giving rise to colour change and punch filming during tabletting. In short, the hemisulphate polymorphs described in ""323 were considered unsuitable for the preparation of solid dosage forms.
International Patent Application PCTI/EP98/04176 is concerned with aqueous pharmaceutical compositions comprising the preferred hydrobromide polymorph identified in ""323 and describes for the purposes of comparison the preparation of a corresponding hemisulphate composition. The hemisulphate salt used for the preparation of said composition is the xcex2-polymorph described in ""323.
We have now unexpectedly found that there exists a third polymorph of the hemisulphate salt of 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole which overcomes the disadvantages associated with the xcex1- and xcex2-forms described in European Patent 0776323. Furthermore, it has advantages over the preferred polymorph of the corresponding hydrobromide salt in terms of liquid dosage preparation.
Thus the problem addressed by the present invention is to provide a pharmaceutically acceptable hemisulphate salt of 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole which may be efficiently processed to provide stable and effective pharmaceutical compositions, particularly those in solid or liquid dosage form. Important criteria to be satisfied are, inter alia, that the selected salt should be crystalline, non-hygroscopic and compressible, possess solid-state stability, be of suitable melting point and have acceptable solubility characteristics.
As indicated, this problem has been solved by the surprising finding of a novel polymorphic form of the hemisulphate salt of 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole which meets the foregoing requirements, overcomes the disadvantages associated with the xcex1- and xcex2-polymorphs described in European Patent 0776323 and has advantages with regard to solubility and the ability to prepare liquid dosage forms over the preferred polymorph of the corresponding hydrobromide salt.
Thus according to the present invention, there is provided a crystalline, polymorphic form of a compound of formula (I) characterised by a powder X-ray diffraction (PXRD) pattern having main peaks at 9.28, 10.38, 11.37, 12.40, 16.84, 17.46, 17.53, 17.78, 17.98, 19.48, 20.70, 21.29, 21.45, 22.21, 22.64, 23.08, 25.20 and 25.79.
The polymorph of the invention is further characterised by its infrared (IR) spectrum which shows significant absorption bands at "ugr"=3385.3, 3172.0, 3143.8, 3058.0, 3022.6, 2954.8, 2928.3, 2893.5, 2650.7, 2436.4, 1622.6, 1584.1, 1480.8, 1445.6, 1362.4, 1354.4, 1304.8, 1246.0, 1229.9, 1164.3, 1149.6, 1137.5, 1087.1, 1071.7, 1019.5, 958.9, 929.8, 899.1, 878.9, 842.6, 793.8, 759.3, 751.4, 731.3, 690.4, 619.9, 606.3, 564.9, 533.7, 512.2, 503.6, 485.3, 457.5 and 428.9 cmxe2x88x921.
The polymorph of the invention is yet further characterised by its Differential Scanning Calorimetry (DSC) trace which shows a sharp endotherm at 226xc2x0 C. corresponding to its melting point.
In marked contrast to the xcex1- and xcex2-polymorphs, the hemisulphate polymorph of the present invention shows negligible hygroscopicity, no change in its polymorphic form after seven months as demonstrated by Powder X-Ray Diffraction (PXRD) and Differential Scanning Calorimetry (DSC) and no significant colour change or punch filming upon compression. At pH 4.0, the polymorph of the invention has a solubility very similar to that of the preferred hydrobromide of ""323, but at the more biologically significant pH 6.0 its solubility increases to 478 mg/ml compared to 2.90 mg/ml for the hydrobromide.
The foregoing properties render the polymorph of the invention eminently suitable for the preparation of pharmaceutical compositions, particularly those in solid or liquid dosage form. Thus, according to a further aspect of the present invention, the polymorph of the invention and pharmaceutical compositions thereof are provided for use as medicaments.
The present invention also provides processes for the preparation of said polymorph, either in a single solvent or by reprocessing the initially-formed product in a different solvent. Reprocessing typically takes the form of refluxing the initially-formed product in a different solvent followed by isolation of the desired polymorph.
The polymorph of the invention may, for example, be obtained by
(i) treatment of a solution of 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole in a first suitable solvent, for example, acetone or tetrahydrofuran, with concentrated sulphuric acid, typically at a temperature of from xe2x88x922 to 2xc2x0 C., followed by heating under reflux in the same solvent; or by
(ii) treatment of a solution of 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole in a first suitable solvent, typically acetone, with concentrated sulphuric acid, typically at a temperature of from xe2x88x922 to 2xc2x0 C., followed by isolation of the resulting slurry and reprocessing in a second suitable solvent, for example, tetrahydrofuran.
In both cases, the resulting solution is cooled and the desired polymorph isolated. Seeding may be employed to induce crystallisation, but this is usually unnecessary.
According to a further aspect of the present invention, there are provided pharmaceutical compositions comprising the hemisulphate polymorph of the invention together with a pharmaceutically acceptable excipient, diluent, or carrier.
Thus the compound of the invention may be administered alone, but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent, or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
For example, the compound of the invention may be administered orally, buccally, or sublingually in the form of optionally flavoured and/or coloured tablets, capsules, ovules, elixirs, solutions, or suspensions suitable for immediate, delayed, or controlled release applications. The compound may also be administered by intracavernosal injection.
Such tablets may contain excipients, such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, or glycine, disintegrants, such as starch (preferably corn, potato, or tapioca starch), sodium starch glycollate, croscarmellose sodium or certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin, or acacia. Additionally, lubricating agents, such as magnesium stearate, stearic acid, glyceryl behenate, or talc may be included.
Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar, or a high molecular weight polyethylene glycol. For aqueous suspensions and/or elixirs, the compound may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents, such as water, ethanol, propylene glycol, or glycerin, or combinations thereof.
The compound may also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intrastemally, intracranially, intramuscularly, or subcutaneously, or it may be administered by infusion techniques. It is best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. If necessary, the aqueous solutions may be suitably buffered, preferably to a pH of from 3 to 9. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
For oral and parenteral administration to human patients, the daily dosage level of the compounds of the formula (I) will usually be from 0.01 mg to 20 mg/kg (in single or divided doses).
Thus tablets or capsules of the compound of the invention may contain from 0.5 mg to 0.5 g of active compound for administration either singly or two or more at a time as appropriate. The physician in any event will determine the actual dosage which will be most suitable for any individual patient and it may vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
The compound of the invention may also be administered intranasally or by inhalation and is conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, or nebuliser using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane, such as 1,1,1,2-tetrafluoroethane (HFA 134A(trademark) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA(trademark), carbon dioxide, or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray, or nebuliser may contain a solution or suspension of the active compound, for example, by using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, for example, sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.
Aerosol or dry powder formulations are preferably arranged so that each metered dose or xe2x80x98puffxe2x80x99 contains from 25 xcexcg to 10 mg of a compound of the formula (I) for delivery to the patient. The overall daily dose with an aerosol will be in the range of from 100 xcexcg to 10 mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
Alternatively, the compound of the invention may be administered in the form of a suppository or pessary or it may be applied topically in the form of a lotion, solution, cream, ointment, or dusting powder. The compound may also be administered transdermally, for example, by means of a skin patch, or by the ocular route.
For ocular administration, the compound may be formulated as micronised suspensions in isotonic, pH-adjusted, sterile saline or, preferably, as solutions in isotonic, pH-adjusted, sterile saline, optionally in combination with a preservative, such as a benzylalkonium chloride. Alternatively, it may be formulated in an ointment, such as petrolatum.
For topical application to the skin, the compound of the invention may be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, or water. Alternatively, it may be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, or water.
Particularly preferred compositions in accordance with the invention include conventional, controlled release and fast dispersion tablets and intranasal and intravenous solutions, all of which may readily be prepared by conventional means using the polymorph of the invention.
Finally, the invention provides for the use of the hemisulphate polymorph of the invention for the manufacture of a medicament for the curative or prophylactic treatment of a medical condition for which an agonist of 5-HT1 receptors is indicated and for a method of curative or prophylactic treatment of a medical condition for which an agonist of 5-HT1 receptors is indicated which comprises the administration of a therapeutically effective amount of the hemisulphate polymorph of the invention. Such conditions include migraine and associated conditions such as cluster headache, chronic paroxymal hemicrania and headache associated with a vascular disorder, depression, anxiety, an eating disorder, obesity, drug abuse, hypertension and emesis.